Automated synthesis of a library of triazolated 1,2,5-thiadiazepane 1,1-dioxides via a double aza-Michael strategy

Article abstract of DOI:10.1021/co300049u

The construction of a 96-member library of triazolated 1,2,5-thiadiazepane 1,1-dioxides was performed on a Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 94 out of 96 possible products.

Full text of DOI:10.1021/co300049u

Letter
pubs.acs.org/acscombsci
Automated Synthesis of a Library of Triazolated 1,2,5-Thiadiazepane
1,1-Dioxides via a Double Aza-Michael Strategy
Qin Zang,†,‡ Salim Javed,†,‡ David Hill,‡ Farman Ullah,‡,§ Danse Bi,† Patrick Porubsky,‡
Benjamin Neuenswander,‡ Gerald H. Lushington,‡ Conrad Santini,‡ Michael G. Organ,‡,§
and Paul R. Hanson*,†,‡
†Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, United States
‡The University of Kansas Center for Chemical Methodologies and Library Development (KU-CMLD), 2034 Becker Drive, Del
Shankel Structural Biology Center, Lawrence, Kansas 66047, United States
§Department of Chemistry, York University, 4700 Keele Street, Toronto, ON, M3J 1P3 Canada
S
* Supporting Information
ABSTRACT: The construction of a 96-member library of triazolated 1,2,5-thiadiazepane 1,1-dioxides was performed on a
Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 94 out of
96 possible products. The key step, a one-pot, sequential elimination, double-aza-Michael reaction, and [3 + 2] Huisgen
cycloaddition pathway has been automated and utilized in the production of two sets of triazolated sultam products.
KEYWORDS: aza-Michael, triazolated 1,2,5-thiadiazepane 1,1-dioxides, parallel synthesis
Scheme 1. Previously Reported Click, Click, Cy-Click
Process
utomated synthesis, in which robots and machines carry
Aout much of the bench work, including setting up
reactions, workup, purification, and analysis, has emerged as
the consequence of the growing demand of hit discovery for the
development of therapeutic agents.1,2 Historically, automated
synthesis has found heavy use in the area of peptide synthesis,3
polymer synthesis,4 and carbohydrate synthesis.5 Takahashi and
co-workers utilized an automated synthesizer in a 36-step
formal total synthesis of Taxol.6 The examples of automated
synthesis of complex natural products are further enriched by
the synthesis of grossamide7 and oxomaritidine8 from Ley and
co-workers, as well 9-membered masked enediynes9 and
spiruchostatin B10 from the Takahashi group.
Previously, an inter/intramolecular double aza-Michael
pathway was employed as the cyclization step using tertiary
sulfonamides containing TBS-protected serinol methyl ester
moiety (Scheme 1).11 Automation and scale out of the inter/
intramolecular double aza-Michael addition using a microwave-
assisted, continuous flow organic synthesis platform (MACOS)
further optimized this “Click, Click, Cy-Click” process.12 As an
alternative approach, and as part of a larger program aimed at
the facile production of sulfur-13,14 and phosphorus-containing
heterocyclic libraries for early phase drug discovery, we herein
report the synthesis of a 96-member library of triazolated 1,2,5-
thiadiazepane 1,1-dioxides using a Chemspeed Accelerator
(SLT-100) automated parallel synthesis platform for facile
production of the titled compounds.
Chemical Method. The vinylsulfonamide linchpin 3 was
prepared via sulfonylation of TBS-protected serinol methyl
Received: May 3, 2012
Revised: July 2, 2012
Published: August 1, 2012
© 2012 American Chemical Society
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Letter
Scheme 2. Utilizing a One-Pot, Sequential Elimination, Double-Aza-Michael Reaction, and [3 + 2] Huisgen Cycloaddition in
the Synthesis of Triazolated 1,2,5-Thiadiazepane 1,1-Dioxides
Scheme 3. Automation of a One-Pot, Sequential Elimination, Double Aza-Michael and Huisgen Cycloaddition Step
ester (1), followed by sulfonamide alkylation. This scaffold was
prepared on 5-g scale with a yield of 56% over three steps. A
sequential one-pot elimination, double aza-Michael addition of
eight amines 4{1−8}, and subsequent [3 + 2] Huisgen
cycloaddition with six azides 5{1−6} generated the 48-member
library of 6{1−8, 1−6} (Part A, Scheme 2). Likewise,
vinylsulfonamide linchpins 7{1−6} were prepared in good
yield and on 1-g scale. The orientation of triazole groups were
″flipped″ in producing another set of 48 compounds [8{1−6,
1−8}, Part B] merely by switching to propargyl amine which
serves as both the double aza-Michael reaction donor and
cycloaddition partner with eight azides 5{1−8}.
of undesirable building blocks that led to products with
undesirable in-silico properties.15 These metric filters included
standard Lipinski Rule of 5 parameters16 (molecular weight
<500, ClogP <5.0, number of H-acceptors <10, and number of
H-donors <5), in addition to consideration of the number of
rotatable bonds (<5) and polar surface area. Absorption,
distribution, metabolism, and excretion (ADME) properties
were calculated17 along with diversity analysis using standard
H-aware 3D BCUT descriptors18 comparing against the
MLSMR screening set (ca. 7/2010; ∼330,000 unique chemical
structures).
Automated Library Synthesis. The automated one-pot,
sequential elimination, double aza-Michael and Huisgen
cycloaddition was performed on a Chemspeed Accelerator
Library Design. For selecting building blocks, physico-
chemical property filters were applied, guiding the elimination
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ACS Combinatorial Science
Letter
primary objectives set out in the library design were achieved;
final average mass was obtained as 58 mg with average purity as
94%, and the average yield was 40% (Chart 1). A total of 94
products from the proposed 96-membered library met the
requirements and have been submitted to MLPCN and other
screening partners.
Chart 1. Library: Final Mass, Purity, and Yield
In conclusion, the automated production of a library of 94/96-
member triazolated 1,2,5-thiadiazepane 1,1-dioxides has been
successfully completed. All the procedures of liquid and solid
transferring, reaction stirring and heating, solvent evaporation,
and solid phase extraction (SPE) were automatically carried out
with “no human intervention”, except for software setup and
stock solution preparation. The products have been submitted
for evaluation of their biological activity in high-throughput
screening assays at the NIH MLPCN and the results will be
reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, tabulated results and data for this
library, as well as full characterization for representative
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: phanson@ku.edu. Phone (785) 864-3094. Fax (785)
864-5396.
Notes
The authors declare no competing financial interest.
Financial support of this work was provided by the Institute of
General Medical Sciences (P50-GM069663 and P41-
GM076302), NIH K-INBRE funds (D.B., P20 RR016475),
and the University of Kansas for an Undergraduate Research
Award (D.B.). All are gratefully acknowledged.
(SLT-100) automated parallel synthesis platform. For the
synthesis of 6{1−8, 1−6}, 1 mL of 0.3 M stock solution of
linchpin 3 in MeOH was distributed to each of 48 reactors.
One mL of 0.06 M stock solution of DBU in MeOH was then
added to each reactor, followed by the addition of 1 mL MeOH
solution of 0.33 mmol amines 4{1−8}. The reaction mixture
was heated at 40 °C for 4 h, after which the solvent was
removed under reduced pressure. To the crude products of 9, 2
mL of CH2Cl2 was charged into each reaction vessel, followed
by 0.6 mmol of azide 5{1−6} in 1 mL CH2Cl2. Solid CuI (0.06
mmol) was dispensed into reaction vessels and the reactions
were stirred overnight at room temperature. The mixtures were
then allowed to pass through SPE, flushed with EtOAc, and the
crude products of 6 were collected in bar-coded, preweighted
vials. Compounds 8{1−6, 1−8} were prepared in a similar
process, in which six stock solutions of linchpin 7 was used as
Michael acceptor, and propargyl amine for the double-aza-
Michael donor (Scheme 3).
Result Analysis. The crude products collected in bar-
coded, preweighted vials were concentrated in reduced pressure
and subjected to preparative/mass-directed HPLC purification.
The key to successful library production was to obtain
compounds in >90% purity in 40−50 mg quantities, which
would be sufficient for HTS screening via the Molecular Library
Probe Center Network (MLPCN) (20 mg), external biological
outreach screening partners (20 mg), and to retain a sample
(10 mg) for follow-up evaluation or to resupply the MLPCN.
Final assessment of part A and B demonstrated that these
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